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Metabolism ; 129: 155156, 2022 04.
Article in English | MEDLINE | ID: covidwho-1654927


BACKGROUND: Both obesity and type 2 diabetes (T2D) are reported to be highly enriched in hospitalized COVID-19 patients. Due to the close correlation between obesity and T2D, it is important to examine whether obesity and T2D are independently related to COVID-19 hospitalization. OBJECTIVE: To examine the causal effect of obesity and T2D in hospitalized COVID-19 patients using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS: This two-sample MR analysis applied genetic markers of obesity identified in the genome wide association study (GWAS) by the GIANT Consortium as instrumental variables (IVs) of obesity; and genetic markers of T2D identified by the DIAGRAM Consortium as IVs of T2D. The MR analysis was performed in hospitalized COVID-19 patient by the COVID-19 Host Genetics Initiative using the MR-Base platform. RESULTS: All 3 classes of obesity (Class 1/2/3) were shown as the causal risk factors of COVID-19 hospitalization; however, T2D doesn't increase the risk of hospitalization or critically ill COVID-19 as an independent factor. CONCLUSIONS: Obesity, but not T2D, is a primary risk factor of COVID-19 hospitalization.

COVID-19/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Hospitalization/statistics & numerical data , Mendelian Randomization Analysis , Obesity/epidemiology , SARS-CoV-2 , Body Mass Index , COVID-19/genetics , COVID-19/therapy , Causality , Comorbidity , Diabetes Mellitus, Type 2/genetics , Genome-Wide Association Study , Humans , Obesity/classification , Obesity/genetics , Polymorphism, Single Nucleotide/genetics , Risk Factors , Severity of Illness Index
Preprint in English | Other preprints | ID: ppcovidwho-295773


Objective The cytokines, LIGHT (TNFSF14) and Interleukin-18 (IL-18), are two important therapeutic targets due to their central roles in the function of activated T cells and inflammatory injury. LIGHT was recently shown to play a major role in COVID19 induced acute respiratory distress syndrome (ARDS), reducing mortality and hospital stay. This study aims to investigate the associations of LIGHT and IL-18 with non-COVID19 related ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), secondary to viral or bacterial sepsis. Research Design and Methods A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this study and compared to healthy controls. Serum LIGHT, IL-18, and 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured and associated with symptom severity. Results ARDS was observed in 36% of the patients, with 29% of the total patient cohort developing multi-organ failure (failure of two or more organs). We observed significantly increased LIGHT level (>2SD above mean of healthy subjects) in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures, suggesting LIGHT may be an inflammatory driver. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis. Conclusions For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. LIGHT levels are significantly elevated in non-COVID19 sepsis patients with ARDS and/or multi-organ failures suggesting that anti-LIGHT therapy may be effective therapy in a subset of patients with sepsis. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway raises opportunities that require a precision application.